The incidence of thyroid cancer has continued to increase each year in the United States such that in 2010 it ranked as the 5th most diagnosed cancer in women. Among several subtypes, medullary thyroid carcinoma (MTC) represents 2-5% of thyroid cancer cases. Despite this low frequency, there is a disproportionate number of deaths from MTC compared with other thyroid cancers. MTC has a 50% mortality rate at 4 years in patients with metastatic or recurrent disease. In patients with progressive metastatic disease, treatment with vandetanib, a tyrosine kinase inhibitor (TKI), improves progression-free survival, and other TKIs may also be beneficial. Vandetanib, which specifically targets RET and angiogenesis, has become the new standard of care for MTC patients with symptomatic and progressing disease. Unfortunately, there are currently no measures to predict who will respond to TKI treatment, or to identify tumor progression, development of drug resistance or monitor potential for recurrence at an early stage. We believe that the inability to identify those patients who will progress earlier in the course of their disease and to select rationally a specific TKI treatment limits potential for response and benefit. The measurement of cell-free DNA and the profiling of circulating tumor cells has emerged as a biological measure with direct relevance to cancer development, progression and resistance to therapy. We hypothesize that levels of circulating DNA and/or cellular expression profiles provides a direct and predictive measure of total metastatic potential. Furthermore, use of these measurements should allow personalization of drug choice, timing of treatment, and guide withdrawal from treatment, which will lead to better patient outcomes compared with existing approaches. The specific aims to address these needs include: (1) Develop blood-based assays capable of assessing prognosis, metastatic potential, and response to treatment, (2) Comparative evaluation of assays as predictors/indicators of therapeutic response. These aims derive from an extensive MTC treatment and research experience, and build upon an emerging wealth of data in other cancers. The completed studies will derive new tools that may offer greater therapeutic benefit through enhanced specificity of drug targeting. RELEVANCE (See instructions): Thyroid cancer incidence continues to increase annually despite the fact that new discoveries have led to reductions in most cancer types. Recent studies suggest that tumor metastasis and recurrence is driven by a subpopulation of cells that are capable of seeding local and distant regrowth of tumors. This proposal seeks to develop new assays to detect tumor cells and evidence of tumor cell death in patient blood samples. These novel assays will be used to determine patient response to treatment.